Pd-catalyzed C-H fluorination with nucleophilic fluoride

Article abstract of DOI:10.1021/ol301739f

The palladium-catalyzed C-H fluorination of 8-methylquinoline derivatives with nucleophilic fluoride is reported. This transformation involves the use of AgF as the fluoride source in combination with a hypervalent iodine oxidant. Both the scope and mechanism of the reaction are discussed.

Full text of DOI:10.1021/ol301739f

ORGANIC
LETTERS
2012
Vol. 14, No. 16
4094–4097
Pd-Catalyzed CꢀH Fluorination with
Nucleophilic Fluoride
Kate B. McMurtrey, Joy M. Racowski, and Melanie S. Sanford*
University of Michigan, Department of Chemistry, 930 North University Avenue, Ann
Arbor, Michigan 48109-1055, United States
mssanfor@umich.edu
Received June 25, 2012
ABSTRACT
The palladium-catalyzed CꢀH fluorination of 8-methylquinoline derivatives with nucleophilic fluoride is reported. This transformation involves the
use of AgF as the fluoride source in combination with a hypervalent iodine oxidant. Both the scope and mechanism of the reaction are discussed.
The substitution of hydrogen with fluorine can have a
dramatic impact on the lipophilicity, metabolism, and
overall biological activity of organic molecules.1 As a
result, carbonꢀfluorine bonds feature prominently in
pharmaceuticals, agrochemicals, and PET imaging re-
agents. However, despite the prevalence and great utility
of this functional group, synthetic methods for forming
CꢀF bonds under mild conditions remain limited.2
Transition-metal-catalyzed CꢀF coupling reactions are
particularly rare and constitute powerful synthetic tools
to complement more conventional methods. In particular,
efficient catalytic fluorination via either cross-coupling3ꢀ6
or CꢀH functionalization7,8 can facilitate the late stage
introduction of fluorine into biologically active molecules.
This is of great value for both SAR studies and for
radiolabeling applications (since t1/2 for 18F is approxi-
mately 110 min).2
We and others have previously reported the Pd-cata-
lyzed conversion of CꢀH bonds to CꢀF bonds using
electrophilic fluorinating reagents (abbreviated Fþ re-
agents or OxidantꢀF throughout this manuscript).7,8
These reactions are believed to proceed via a catalytic cycle
such as that shown in Scheme 1, where CꢀF bond-forming
reductive elimination from PdIV(R)(F) (D)9,10 serves as a
key step. Thus the role of the Fþ reagent is twofold: (1) it
oxidizes the PdII to PdIV (step ii), and (2) it serves as the
source offluorinethatends upin the finalproduct(stepiii).
While this first-generation approach to CꢀH fluorina-
tion was successful, these reactions suffer from the distinct
disadvantage that they require electrophilic fluorinating
reagents. Even though a number of Fþ sources are com-
mercially available, they are often much more expensive
(1) For recent reviews, see: (a) Jeschke, P. Pest Manag. Sci. 2010, 66,
10. (b) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc.
Rev. 2008, 37, 320.
(2) For recent reviews, see: (a) Hollingworth, C.; Gouverneur, V.
Chem. Commun. 2012, 48, 2929. (b) Furuya, T.; Kamlet, A. S.; Ritter, T.
Nature 2011, 473, 7348. (c) Furuya, T.; Kuttruff, C. A.; Ritter, T. Curr.
Opin. Drug Discovery Dev. 2008, 11, 803.
(3) (a) Maimone, T. J.; Milner, P. J.; Kinzel, T.; Zhang, Y.; Takase,
M. K.; Buchwald, S. L. J. Am. Chem. Soc. 2011, 133, 18106. (b) Noel, T.;
Maimone, T. J.; Buchwald, S. L. Angew. Chem., Int. Ed. 2011, 50, 8900.
(c) Watson, D. A.; Su, M.; Teverovskiy, G.; Zhang, Y.; Garcia-Fortanet,
J.; Kinzel, T.; Buchwald, S. L. Science 2009, 321, 1661.
(4) (a) Topczewski, J. J.; Tewson, T. J.; Nguyen, H. M. J. Am. Chem.
Soc. 2011, 133, 19318. (b) Katcher, M. H.; Sha, A.; Doyle, A. G. J. Am.
Chem. Soc. 2011, 133, 15902. (c) Hollingworth, C.; Hazari, A.; Hopkin-
son, M. N.; Tredwell, M.; Benedetto, E.; Huiban, M.; Gee, A. D.;
Brown, J. M.; Gouverneur, V. Angew. Chem., Int. Ed. 2011, 50, 2613. (d)
Katcher, M. H.; Doyle, A. G. J. Am. Chem. Soc. 2010, 132, 17402.
(5) Casitas, A.; Canta, M.; Sola, M.; Costas, M.; Ribas, X. J. Am.
Chem. Soc. 2011, 133, 19386.
(8) (a) Chan, C. S. L.; Wasa, M.; Wang, X.; Yu, J. Q. Angew. Chem.,
Int. Ed. 2011, 50, 9081. (b) Wang, X.; Mei, T. S.; Yu, J. Q. J. Am. Chem.
Soc. 2009, 131, 7520.
(9) For examples of CꢀF bond formation from PdIV(R)(F) species,
see: (a) Racowski, J. M.; Kampf, J. W.; Sanford, M. S. Angew. Chem.,
Int. Ed. 2012, 51, 3414. (b) Ball, N. D.; Kampf, J. W.; Sanford, M. S. J.
Am. Chem. Soc. 2010, 132, 2878. (c) Furuya, T.; Benitez, D.; Tkatchouk,
E.; Strom, A. E.; Tang, P.; Goddard, W. A.; Ritter, T. J. Am. Chem. Soc.
2010, 132, 3793.
(6) Tang, P.; Furuya, T.; Ritter, T. J. Am. Chem. Soc. 2010, 132,
12150.
(7) Hull, K. L.; Anani, W. Q.; Sanford, M. S. J. Am. Chem. Soc. 2006,
128, 7134.
(10) Hickman, A. J.; Sanford, M. S. Nature 2012, 484, 177.
r
10.1021/ol301739f
Published on Web 07/30/2012
2012 American Chemical Society

Scheme 1. Pd-Catalyzed CꢀH Fluorination with Fþ Reagents
Scheme 2. Proposed Sequence
than fluoride reagents. For example, the Sigma-Aldrich
prices for N-fluoropyridinium salts (NFPs) and Selectfluor
(both Fþ reagents) are several orders of magnitude more
expensive than CsF and KF (Figure 1). In addition,
commonly used Fþ reagents such as NFPs and Selectfluor
generate large quantities of organic waste and exhibit
modest tolerance to nucleophilic functional groups. Final-
ly, electrophilic fluorinating reagents are much less desir-
able than fluoride for PET imaging applications, because
18Fꢀ has significantly higher specific activity than 18Fþ
precursors.2
approach. As shown in eq 1, Liu and co-workers demon-
strated this transformation using PhI(OPiv)2 as an oxidant
in conjunction with AgF as a nucleophilic fluoride
source.12 We describe herein the use of a similar strategy
to achieve the Pd-catalyzed ligand-directed CꢀH fluorina-
tion of 8-methylquinoline derivatives using the combina-
tion of hypervalent iodine reagents and fluoride salts.
Our initial studies focused on the CꢀH fluorination of
8-methylquinoline, since this is an excellent substrate for
Pd-catalyzed fluorination with Fþ reagents.7 The use of
10 mol % of Pd(OAc)2 along with PhI(OAc)2 and AgF in
MeCN at 25 °C for 24 h provided a modest yield of the
desired fluorinated product 1a (14%), along with the
corresponding CꢀH oxygenation product 2a (17%) and
recovered starting material (61%).13,14 Increasing the tem-
perature to 60 °C resulted in nearly complete conversion of
8-methylquinoline; however, the yield of the desired fluori-
nated product remained low (14%) (Table 1, entry 1).
Changing the oxidant from PhI(OAc)2 to PhI(OPiv)2 and
the solvent from MeCN to CH2Cl2 resulted in quantitative
conversion of 8-methylquinoline and provided a 58% yield
of 1a (entry 3).
Figure 1. Prices for commercial fluorine sources (based on
largest quantity available from Sigma Aldrich in >95%
purity).
We hypothesized that Pd-catalyzed CꢀH fluorination
with nucleophilic fluoride could be accomplished by separ-
ating the two roles played by the Fþ reagent in these
transformations.11 As shown in Scheme 2, an external
oxidant could be used to convert PdII to PdIV (step ii)
while a fluoride source could provide a ligand to PdIV that
would ultimately participate in CꢀF bond-forming reduc-
tive elimination (step iii).
The major side product in this transformation (2a)
derives from CꢀH oxygenation of the 8-methylquinoline.15
While products 1a and 2a are easily separable by column
chromatography on silica gel, it would clearly be desirable
to obtain higher yields of 1a in these transformations. We
initially hypothesized that the electronic/steric properties
A recent report on Pd-catalyzed alkene aminofluorina-
tion provided preliminary support for the viability of this
(12) Wu, T.; Yin, G.; Liu, G. J. Am. Chem. Soc. 2009, 131, 16354.
(13) Importantly, control reactions show that 1a and 2a do not
interconvert under the reaction conditions, indicating that they are not
formed from one another in this transformation (see p S8 of the
Supporting Information for details).
ꢀ(11) For related “umpolung” strategies to achieve fluorination with
F
reagents, see: (a) Gao, Z.; Lim, Y. H.; Tredwell, M.; Li, L.; Verhoog,
(14) By analogy to Liu’s work, MgSO4 was also added. The role of
this additive is likely to remove water.
(15) Dick, A. R.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004,
124, 2300.
S.; Hopkinson, M.; Kaluza, W.; Collier, T. L.; Passchier, J.; Huiban, M.;
Gouverneur, V. Angew. Chem., Int. Ed. 2012, 51, 6733. (b) Lee, E.;
Kamlet, A. S.; Powers, D. C.; Neumann, C. N.; Boursalian, G. B.;
Furuya, T.; Choi, D. C.; Hooker, J. M.; Ritter, T. Science 2011, 334, 639.
Org. Lett., Vol. 14, No. 16, 2012
4095

of R in the hypervalent iodine reagent could be tuned
to enhance the yield of 1a. However, examination of 19
different R substituents revealed that PhI(OPiv)2 provides
the best results (see Table S4 for complete details). Sig-
nificant additional experimentation led to the discovery
that the yield of 1a could be enhanced by modification of
the reaction conditions. Specifically, prestirring the PhI-
(OPiv)2 and AgF in CH2Cl2 for 1 h at 60 °C before adding
the Pd catalyst, substrate, and MgSO4 resulted in a modest
boost in the yield of 1a as well as an improved ratio of 1a/
2a (entry 4). Importantly, all of these reactions were set up
on the benchtop using commercially available reagents
the success of the desired fluorination reaction. Assuch, we
examined the use of an exogenous Ag(I) salt in conjunction
with CsF.17 Gratifyingly, the Pd-catalyzed CꢀH fluorina-
tion proceeded to afford 1a in 45% yield under these
conditions (eq 2).
The scope of Pd-catalyzed nucleophilic CꢀH fluorina-
tion was evaluated with a variety of 8-methylquinoline
derivatives. As shown in Table 2, diverse substituents at
positions X and Y were tolerated. Most notably, a variety
of halogens were compatible with the reaction conditions
(entries 5ꢀ8), providing sites for further elaboration of the
products. In general, the best results were obtained when X
and Y were electron-withdrawing groups (entries 2ꢀ8).
Significantly lower yields of the fluorinated product were
observed when X = phenyl or methyl (entries 9, 10);
furthermore, the substrate with X = methoxy afforded
<1% of 1k. Notably, in all cases, the CꢀH oxygenation
product (analogue of 2a) was the major side product.
Table 1. Optimization of CꢀH Fluorination with PhI(O2CR)2/
MF
yield (%)a
conversion
entry
solvent
R
M
(%)
1a
2a
1
MeCN
Me
tBu
tBu
tBu
tBu
tBu
tBu
tBu
Ag
87
32
14
8
64
14
25
18
6
2
MeCN
Ag
Ag
Ag
Cs
3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
100
100
9
58
62
<1
<1
<1
<1
4b
5b
6b
7b
8b
Table 2. Substrate Scope of CꢀH Fluorination of 8-Methyl-
quinoline Derivatives
Rb
K
15
14
15
11
19
NBu4
25
a Yields determined by GC based on an average of at least two runs.
b AgF and PhI(OPiv)2 were prestirred at 60 °C for 1 h in CH2Cl2 prior to
addition of the rest of the reagents.
GC yield
(%)
isolated
without any drying or prepurification. This is relatively
rare for a nucleophilic fluorination reaction.2
entry
X
Y
product
yield (%)
1
H
H
H
H
H
H
H
Br
H
H
H
H
1a
1b
1c
1d
1e
1f
67
62
67
59
44
53
49
67
43
41
<1
49
41
70
59
30
44
42
55
39
39
nd
The optimal conditions in Table 1 require 24h toachieve
maximum yield. Such long reaction times are undesirable
for PET imaging applications because the half-life of 18F is
short (∼110 min). Thus, we also examined a variety of
approaches to accelerate this transformation. Gratify-
ingly, when the temperature was increased to 80 °C, a
40% yield of product 1acould be obtained after just 15min
under the PhI(OPiv)2/AgF conditions.
It would also be attractive to replace AgF with an
alternative fluoride source. This would be particularly
useful in the context of PET imaging applications, where
the most readily available 18Fꢀ starting materials are CsF,
RbF, NBu4F, and KF-Kryptofix.16 However, as shown in
Table 1, entries 5ꢀ8, the substitution of AgF with CsF,
RbF, NBu4F, or KF under our optimized reaction condi-
tions led to <1% yield of the fluorinated product. These
results suggest that the presence of Ag(I) is important for
2a
3
NO2
CN
CO2CH3
F
4a
5
6
Br
7
H
1g
1h
1i
8a
9b,c
10c
11a
I
Ph
Me
MeO
1j
1k
a The reaction was run for 24 h. b The reaction was run for 28 h. c PhF
was used as a solvent in place of CH2Cl2.
We hypothesize that high valent Pd-alkyl fluorides of
general structure B are key intermediates in this process.
There are at least two possible pathways for accessing such
(17) Low yields were obtained when CsF was replaced with other
fluoride salts (NaF, TBAF, or KF).
(16) Schlyer, D. J. Ann. Acad. Med. Singapore 2004, 33, 146.
4096
Org. Lett., Vol. 14, No. 16, 2012

that this iodine(III) reagent is formed under the reaction
conditions.
We next independently synthesized a pure sample
Scheme 3. Two Possible Routes to B from A, AgF, and ArI-
(OPiv)2
21
of p-MeC6H4IF2 to establish whether it is effective
at promoting CꢀH fluorination in the absence of
p-MeC6H4I(OPiv)2/AgF. Intriguingly, the use of 2 equiv
of p-MeC6H4IF2 in place of p-MeC6H4I(OPiv)2/AgF un-
der otherwise analogous conditions afforded only a 7%
yield of 1a along with 42% recovered starting material.22
Finally, the combination of 2 equiv of p-MeC6H4IF2 and
3 equiv of AgF did not enhance the yield, instead providing
6% of 1a and 27% starting material. Collectively, these
results suggest that, while ArIF2 is present under these
reaction conditions, it is not the primary active fluorinating
reagent in this transformation. More detailed investigations
will be required to establish a comprehensive mechanistic
understanding of this transformation.23
In conclusion, we have demonstrated a transformation
that is, to our knowledge, the first example of palladium-
catalyzed CꢀH fluorination using nucleophilic fluoride.
The fluoride source can be either AgF or CsF (the latter in
combination withAgOTf). The reactions typically proceed
in modest to good yield over 24 h, and the use of a higher
reaction temperature leads to the formation of significant
quantities of fluorinated product in just 15 min. Ongoing
work in our laboratory will probe the mechanism and
expand the scope of this transformation to diverse CꢀH
substrates.
species under the current reaction conditions. A first would
involve the oxidation of cyclometalated PdII complex A by
PhI(OPiv)2 followed by ligand substitution of pivalate for
fluoride at the resultant PdIV intermediate (Scheme 3,
pathway 1). A second pathway would proceed via initial
substitution of pivalate for fluorideatthe iodine(III) center
followed by oxidation of Awith PhIF2 (Scheme 3, pathway 2).
Notably, a recent report by DiMagno demonstrated that
the treatment of PhI(OAc)2 with rigorously dry TBAF
affords PhIF2 in high yield.18 This precedent suggests the
potential plausibility of pathway 2.
Acknowledgment. Thisworkwas supportedbythe NIH
NIGMS (GM073836). We thank Dr. Nicholas Ball (recent
PhD recipient from MSS group) for the synthesis of
7-bromo-8-methylquinoline.
To gain preliminary insights into the mechanism,
we monitored the reaction by 19F NMR spectroscopy
using iodotoluene dipivalate [p-MeC6H4I(OPiv)2] as the
oxidant.19 Analysis of the crude reaction mixture after
prestirring 1 equiv of p-MeC6H4I(OPiv)2 with 2.5 equiv of
AgF for 30 min at 60 °C in CD2Cl2 showed a new
resonance at ꢀ176 ppm.20 This signal corresponds to the
literature value18 as well as to that obtained for an authen-
tic sample of p-MeC6H4IF2, providing strong evidence
Supporting Information Available. Experimental de-
tails and spectroscopic and analytical data for new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(21) Shreeve, J. M.; Ye, C.; Twamley, B. Org. Lett. 2005, 7, 3961.
(22) Batchwise addition of p-MeC6H4IF2 (three batches over 1 h in
CH2Cl2) afforded very similar results.
(23) One possibility to be investigated is that the compound showing
the 19F NMR resonance at 129.6 ppm [ref 20] is serving as the active
fluorinating reagent in this transformation.
(18) Sun, H.; Wang, B.; DiMagno, S. G. Org. Lett. 2008, 10, 4413.
(19) Under our standard reaction conditions p-MeC6H4I(OPiv)2
performs nearly identically to PhI(OPiv)2, providing 1a and 2a in 63%
and 19% yield, respectively, in the Pd-catalyzed CꢀH fluorination of
8-methylquinoline.
(20) A second resonance at 129.6 ppm is also visible in the 19F NMR
spectrum of the prestirred reaction mixture. The identity of this species
has not yet been definitively established.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 16, 2012
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